The past decade has seen an enormous global scale-up of antiretroviral therapy (ART). Although this widespread distribution of ART has dramatically reduced HIV/AIDs-related mortality, current data suggests that up to 24% of individuals receiving 1st-line ART in sub-Saharan Africa experience virologic failure within 12 months of initiation of therapy. Between 53 to 90% of these have viruses with clinically important HIV-1 drug resistance mutations. As such, antiretroviral drug resistance is one of the main threats to the global control of HIV-1. Due to the extensive use of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), there has been a significant increase in NNRTI drug resistance, and transmitted NNRTI drug resistance, in regions of sub-Saharan Africa. Despite the escalating frequency of NNRTI-resistant variants present in ART-na?ve and - experienced HIV-infected individuals, the next-generation diarylpyrimidine (DAPY) NNRTIs - dapivirine (TMC120), etravirine (ETV) and rilpivirine (RIL) are expected to be increasingly used for the treatment and prevention of HIV-1 infection in resource-limited settings. Indeed, many sub-Saharan Africa countries already have access to ETV, which has been approved for the treatment of HIV-infection in ART-experienced individuals. RIL, which has been co-formulated with emtricitabine and tenofovir, is pending approval as a 1st- line ART regimen in sub-Saharan Africa. A long-acting RIL formulation is also in development as a pre- exposure prophylaxis agent for use in resource-limited settings. Finally, the ASPIRE study is currently assessing whether TMC120 can safely prevent HIV-1 infection when continuously released in the vagina from a silicone ring replaced once a month. The majority of research into HIV-1 drug resistance has focused on subtype B viruses, yet non-subtype B strains are responsible for 90% of global infections. Importantly, there is increasing evidence of subtype differences in drug resistance. As such, the primary goals of this project are to study the resistance and cross-resistance pathways for RIL, ETV and TMC120 in non-subtype B viruses.